PROJECT SUMMARY Glaucoma is a leading cause of blindness. Early diagnosis and close monitoring of glaucoma are important because the onset is insidious and the damage is irreversible. Advanced imaging modalities such as optical coherence tomography (OCT) have been used in the past 2 decades to improve the objective evaluation of glaucoma. OCT has higher axial spatial resolution than other posterior eye imaging modalities, and it has relatively good diagnostic accuracy and reproducibility in the measurement of neural structures damaged by glaucoma. However, the measurement of structure alone, with any imaging modality, has limited sensitivity for detecting early glaucoma and only moderate correlation with visual field (VF) loss. Using high-speed OCT systems, we have developed new methods to image and measure optic nerve head (ONH) and retinal blood flow. Preliminary results showed that VF loss was more highly correlated with retinal blood flow as measured by OCT than any neural structure measured by OCT or other imaging modality. Accordingly, the goal of the proposed project is to improve the diagnostic and prognostic evaluation of glaucoma by further developing novel functional OCT measurements using ultrahigh-speed (70-100 kHz) OCT technology. The specific aims are: 1. Improve Doppler OCT measurement of retinal blood flow. Multi-circular scans of peripapillary retinal arteries and veins measure total retinal blood flow in 2 seconds. The use of faster OCT systems will allow automated measurement with improved reproducibility. 2. Develop quantitative OCT angiography of the ONH. Three dimensional (3D) OCT angiography has been made practical (3x3 mm scan in 3 seconds) by a novel split-spectrum amplitude-decorrelation algorithm. Preliminary results showed dramatic loss of ONH microcirculation in early glaucoma. Algorithmic improvement in angiography, segmentation, quantification, and automation are planned. 3. Measure nerve structure from the ONH to retinal ganglion cells. By registering several volumetric scans, we have demonstrated complete 3D characterization of the retinal fiber pathway from the ONH to the macula. Fully automated quantification of these structures will be developed. 4. Evaluate advanced OCT technologies in clinical studies. The utility of functional and structural OCT in glaucoma will be evaluated in a longitudinal observational study of 150 glaucoma and healthy subjects. The effect of IOP-lowering surgery on blood flow will be studied in 40 subjects. Retinal blood flow, ONH circulation, optic disc rim volume, peripapillary nerve fiber layer volume, and macular ganglion cell complex volume are all pieces of the same glaucoma puzzle. This project will develop novel imaging methods that allow us to look at the whole picture using one tool - ultrahigh-speed OCT.